Folic acid is a B vitamin found in many foods. The term folate refers to folic acid and a large family of related compounds. The term folic acid, folate or folacin are the generic terms used for a group of heterocyclic compounds based on the 4-[(pteridin-6-ylmethyl)amino]benzoic acid skeleton conjugated with one or more L-glutamate units. The definition of the term “folic acid” by the IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) states: “The term folates may also be used in the generic sense to designate any members of the family of pteroylglutamates, or mixtures of them, having various levels of reduction of the pteridine ring, one-carbon substitutions and numbers of glutamate residues.”
Folates are an important component of the human diet, and several adverse health effects can occur if there is a folate deficiency in the diet. Folates are widely distributed in almost all natural foods, but the highest concentrations are found in yeast, liver, fresh green leafy vegetables, asparagus and lettuce. Moderate sources include beef, veal and wheat. Deficiencies in folic acid levels can result from improper diet, diseases of the upper small intestine (for example, celiac disease or tropical sprue) or increased physical demands (for example, pregnancy, infancy, adolescence or alcoholism).
For people having a folic acid deficiency, biochemical abnormalities may be observed in addition to reductions in blood folic acid and erythrocyte concentrations. The primary role of folic acid is in the metabolism of compounds by transfer of a one carbon group from one compound to another in a process referred to as methylation. Folic acid is required for enzymes that are involved in nucleic acid synthesis and subsequent DNA synthesis. Therefore, deficiency of folic acid may result in neural tube defects, reduced production of pyrimidines, reduced catabolism of serine, tryptophan and histidine, and elevation of homocysteine. Folic acid has a long history of use, in conjunction with vitamin B12, for treatment of macrocytic (or megaloblastic) anemia.
Folic acid deficiencies are generally addressed by enriching foods in folates or by use of dietary supplements containing folates. However, the form of folate used to enrich foods and used in dietary supplements is not the form typically found in foods. The folates found in foodstuffs are typically polyglutamates. Synthetic folates used in dietary supplements and to enrich foods are folic acid or folacin, which contain only one glutamic acid attached to the p-aminobenzoic acid-pteridine ring unit. Therefore, supplements containing synthetic folates may not be effective to meet human metabolic requirements, or to fully correct a folic acid deficiency. Moreover, folic acid supplementation using synthetic folates can mask anemia caused by a vitamin B12 deficiency, which can result in megaloblastic anemia.
While synthetic folates may be processed and used in some people having folate deficiencies, in people who have the 677 TT genotype (that is, in people having a reduced capacity to convert 5,10-methylene-THF to 5-methyltetrahydrofolate), synthetic folates are not processed for use. Methylated, or activated, folates, such as 5-methyltetrahydrofolate (5-MTHF), circumvent the 677 gene defect, and therefore methylated folates are particularly useful in addressing the folate deficiency and higher homocysteine in persons having this gene variant.
5-MTHF, which is also sometimes referred to as Methyltetrahydropteroylglutamic acid or methylfolate, is one of the most prevalent and important folate in foodstuffs. A form of water soluble B vitamin, 5-MTHF is the predominant form of folate in human circulation. In the folic acid family, 5-MTHF is the reduced and methylated form. As with all forms of folic acid, 5-MTHF has vitamin activity. The vitamin activity is based on the presence of a pterin structure and at least one glutamyl residue linked via peptide bonds to p-aminobenzoic acid. Unlike synthetic folic acid, 5-MTHF does not mask a vitamin B12 deficiency. 5-MTHF requires vitamin B12 to be converted to tetrahydrofolate (THF) in order to enter the cell. In the case of a vitamin B12 deficiency, 5-MTHF would not convert into THF, and therefore it would not enter the cell.
Animal pharmacokinetic data indicates that orally administered 5-MTHF is readily absorbed from the intestinal tract without degradation. Intestinal uptake of 5-MTHF is accomplished by both active, carrier-mediated transport and through passive diffusion. The general characteristics of 5-MTHF in intestinal transport are similar to that of folic acid. In blood serum, 5-MTHF is nonspecifically bound to proteins.
As described above, folic acids are involved in one-carbon metabolism, also known as methylation. 5-MTHF is involved in the synthesis of S-adenosylmethionine (SAM-e). A methyl group from 5-MTHF is donated to homocysteine, which produces the essential amino acid methionine. Methionine is converted by methionine adenosine tranferase (MAT) into SAM-e. The one-carbon transfers are also especially important in purine and pyrimidine synthesis.
Folate-mediated methylation of homocysteine requires the presence of methionine synthetase and vitamin B12 (as a cofactor). The methylation reactions are:    1. 5-MTHF+B12 (cobalamin)→CH3-B12 (methylcobalamin)+tetrahydrofolate    2. CH3-B12 (methylcobalamin)+Homocysteine→B12 (cobalamin)+Methionine
Methylation by folic acid is also important for the de novo biosynthesis of the nucleotides purine and pyrimidine. As a result, folic acid plays an important role in DNA replication and cell division.
To avoid the drawbacks associated with folic acid supplements containing synthetic folates, it would be desirable to develop a supplement containing an enhanced level of natural activated folates in a biologically active form. Accordingly, it is an object of the present invention to overcome one or more drawbacks or disadvantages of the prior art by providing a functional food or a nutritional supplement containing an activated folate that is readily absorbed in the intestines of a human, and which is reduced by natural, non-synthetic processes. Other objects and advantages of the present invention will be apparent to those skilled in the art in view of the detailed description of the invention set forth below.